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As the number of cases of dementia is projected to nearly triple by 2050, scientists are striving to understand its underlying causes. Recent research points to a crucial link between mitochondrial dysfunction and dementia risk, opening up promising avenues for early detection and new therapies.

Every 3 seconds, someone in the world develops dementia. Currently, there are approximately 55 million people in the world living with dementia – a number that is expected to nearly triple by 2050. There is no treatment for dementia, and physicians confronted with the disease are limited to treating individuals’ symptoms. Despite decades of research, we still have a limited understanding of the molecular mechanisms driving dementia.

Many scientists have attempted to understand how dementia works by examining the role of mitochondria. The phrase “the mitochondria is the powerhouse of the cell” is often heard throughout high school classrooms. As a refresher, a mitochondria is a type of organelle – a tiny organ inside of a cell – responsible for the production of energy that regulates many processes in our body (adenosine triphosphate, also known as ATP). Mitochondria play a crucial role in maintaining the function of cells in the brain (also known as neurons) and survival. If a mitochondria isn’t working, then there is oxidative stress (which damages cells), impaired energy metabolism, and neuronal death. All of these forms of cellular impairment can contribute to the development and progression of neurodegenerative diseases, which are chronic diseases that impact the nervous system and the brain. As a result, mitochondrial dysfunction is often linked with the progression of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. 

A recent study looked into the relationship between mitochondrial dysfunction and dementia risk. Here, researchers analyzed the genetic determinants of mitochondrial DNA copy number (mtDNA-CN) – a measure of mitochondrial function – in a large population cohort from the UK Biobank to try and understand the underlying genetic factors associated with the genetic risk of dementia. Scientists ultimately found a potential causal link between low mtDNA-CN and increased risk of dementia. Though dysfunctional mitochondria have been previously implicated in dementia, this is the first evidence using Mendelian methods demonstrating a causal link. This finding suggests that mtDNA-CN could serve as a marker for early detection of dementia, which opens new possibilities for timely interventions to slow disease progression.

One challenge in mitochondrial genetics is finding a scalable method for estimating mtDNA-CN in large population studies. To overcome this hurdle, researchers developed a method – AutoMitoC – to accurately estimate the amount of mtDNA-CN. Ultimately, this study revealed 71 genetic regions associated with mtDNA-CN from studies involving nearly 400,000 participants.

Identifying genetic variants that influence mtDNA-CN levels allowed for insights into the regulation of mitochondrial function. In particular, researchers found that rare variants in SAMHD1 gene were associated with higher mtDNA-CN levels, offering a potential therapeutic target for parents with mitochondrial DNA depletion disorders. However, these individuals were also found to have an increased risk of breast cancer, highlighting the complex interplay between mitochondrial function and disease susceptibility.

By elucidating the genetic basis of the relationship between mitochondrial function and disease risk, this study offers new avenues for therapeutic development, and underscores the importance of understanding the role of mitochondrial dysfunction, even in diseases such as dementia. As we continue to unravel the complexities of mitochondrial biology, the potential for improving diagnosis, treatment, and prevention of diseases associated with mitochondrial dysfunction – diseases that impact about 1 in every 5,000 people yearly in the United States – become increasingly promising.

Edited by Aanchal Saxena and Jameson Blount